By John E. Voliva, RPh, IACP Executive Vice President

Last week, IACP sent out a member alert about the FDA’s notice of final rulemaking for the “list of drug products that may not be compounded under certain sections of the Food, Drug, and Cosmetic Act (FD&C Act).” This list has been commonly referred to in the pharmacy industry as the “negative list” or the “do not compound list”. Since we sent the member alert, we have received many questions about what the list means, why domperidone does not appear on the list (and if it is now allowed for compounding) and what the FDA’s next steps are for this list. This series of articles will serve as a reference point for all of the “lists” FDA has been charged with creating via the Federal law (specifically, Section 503A of the Food, Drug & Cosmetic Act) to provide clarification to the FDA’s actions and regulation on these “lists”.

First things first – why do the lists need to be created?

Section 503A directly charges the FDA to create three lists & the “positive list”, the “negative list” & the “demonstrably difficult list”. Because these lists are directly laid out in the law and the FDA is given the power of passing regulations on these lists, we now have this notice of final rulemaking for the “negative list” published in early October 2016.

Additionally, with these “lists”, the FDA must consult the Pharmacy Compounding Advisory Committee (PCAC) regarding additions or deletions from any of these lists, “unless the Secretary determines that the issuance of such regulations before consultation is necessary to protect the public health.” FDA has published that they believe passing regulations regarding the lists before consulting the PCAC will “rarely be necessary.”

Therefore, this recent action by the FDA regarding the “negative list” is not only required by Federal law, but FDA must follow certain steps to publish or change any of these lists.

The “negative list” – what does it mean?

It’s always good to look at the actual law as a starting point to fully understand what is going on when an agency passes regulations. For the “negative list”, Section 503A states (emphasis added):

“(1) Licensed pharmacist and licensed physician. A drug product may be compounded under subsection (a) if the licensed pharmacist or licensed physician –

… (C) does not compound a drug product that appears on a list published by the Secretary in the Federal Register of drug products that have been withdrawn or removed from the market because such drug products or components of such drug products have been found to be unsafe or not effective;”

This paragraph is what the industry terms as the “negative list” (it’s just easier to call it that than the “list of drug products that have been withdrawn or removed from the market because such drug products… have been found to be unsafe or not effective).”

It’s important to pay attention to the emphasized text above because it gives us clear direction on how the FDA puts this list together. To appear on the list, the drug must have been available on the market, meaning, at some point in the drug’s history, it was FDA approved. This is key to the reason why drugs like domperidone are NOT on this list – the drugs have never been FDA approved. Does this mean pharmacies can now start freely compounding domperidone? Unfortunately, no, and we will explain this issue in a bit because this particular drug is covered by the “positive” list.

So, the “negative” list deals with drugs which were FDA-approved and on the market at some point in time but had been removed from the market because of safety or efficacy. The vast majority, if not all, of the list are drugs that have been removed from the market because of safety issues. Examples include cisapride, diethylstilbesterol (DES), phenformin, phenylpropanolamine (PPA), terfenidine, and chorionic gonadotropin (NOTE: PPA is not on the current list, but it will appear on the list on November 7, 2016). It is important to point out two important facts about this list:

–          The “negative” list ONLY applies to compounding drugs for human use. Thus, compounding items like cisapride, DES and PPA can still be compounded for veterinary patients.

–          Many items on the list have additional limitations. For example,

o   Diethylstilbestrol: All oral and parenteral drug products containing 25 milligrams or more of diethylstilbestrol per unit dose.

o   Gonadotropin, chorionic: All drug products containing chorionic gonadotropins of animal origin.

o   Nitrofurazone: All drug products containing nitrofurazone (except topical drug products formulated for dermatologic application).

This is not an entire list of these special exceptions and pharmacists should frequently check and download the list for reference (note: this list will be updated with the new list on or around November 7, 2016). From the examples provided, a pharmacy can compound DES for human use as long as the unit dose does not exceed 25 mg. We receive a lot of questions about hCG, but the important distinction for this example is that in only applies to hCG of animal original – human recombinant hCG is still OK to compound. And, nitrofuazone is allowed for topical use. There are many other examples of these exceptions throughout the list.

OK – so that is the “negative” list, what about the “positive” list?

So, this list is a bit more complicated than the negative list, believe it or not. Let’s start with what Section 503A says about this list:

“A) compounds the drug product using bulk drug substances, as defined in regulations of the Secretary published at section 207.3(a)(4) of title 21 of the Code of Federal Regulations –

(III) if such a monograph does not exist and the drug substance is not a component of a drug approved by the Secretary, that appear on a list developed by the Secretary through regulations issued by the Secretary under subsection (d)”

Don’t worry about subsection d – this explains the fact that the FDA can put together these lists and must consult the PCAC.

To rewind a bit, Section 503A requires compounders to use bulk drug substances that comply with one of three “buckets” – the bulk drug substance must have a USP or NF monograph OR appear in an FDA approved drug OR appear on the “positive” list. The reason the industry calls this the “positive” list is because items appearing on the list would be allowed to be compounded with, the opposite of what appears on the “negative” list.

It’s important to note now that the FDA calls this list something different than the industry – the “bulks list”. Positive list or bulks list, we are talking about the same thing. FDA has approached the creation of this list by requesting for nominations of bulk drug substances from compounding stakeholders – the general public, pharmacies and healthcare associations. After a couple rounds of nominations, FDA has put together a master list of nominations, which can be found here. The agency has split this bulks list into three categories:

–          Category 1 – Bulk Drug Substances Under Evaluation

–          Category 2 – Bulk Drug Substances that Raise Significant Safety Risks

–          Category 3 – Bulk Drug Substances Nominated Without Adequate Support

Category 1 represents the substances FDA is presenting to the PCAC for their consideration to either add or not add to the “positive” list. To date, the PCAC have considered over 30 different bulk drug substance for inclusion or exclusion from the positive list. We are working to put together a full chart of substances which have already been considered (and the PCAC voting results) along with other items which will be considered in future meetings.

It is important to know that the PCAC recommendation is not binding. The FDA will seriously take the Committee’s vote under consideration, but until final rulemaking is complete (much like what we recently have seen with the “negative” list), the final determination on these substances is still in a state of flux. Also, FDA has announced they will not take enforcement action on any substances appearing in Category 1 until final rulemaking is complete. Therefore, at this point, even if the Committee has voted to not add an item to the positive list, it can still be compounded until rulemaking is complete.

Items which appear in Category 2 should not be compounded and FDA will take enforcement action if a pharmacy is compounding with one of these three substances: domperidone, germanium sesquioxide and quinacrine for intrauterine use. If a pharmacy is found compounding one of these three drugs for a human patient, the FDA will issue the pharmacy a warning letter.

Category 3 is a list of items which the FDA has determined to not have enough supporting information to warrant their presentation to the PCAC. At this time, IACP is working to provide information to “clean up” this list – to remove items which clearly are not bulk drug substances and would never be used in that manner. FDA has announced they would not provide enforcement discretion for these items, however, to date, we have not seen any enforcement actions be taken in regards to these items.

With all of this, we come to a bit of quandary, especially in regards to Category 2. While these items are not on the “negative” list, the FDA still feels these items should not be compounded because of safety risks. Why, then, do these three drugs not appear on the negative list? The answer is pretty simple: they were never FDA approved and never appeared on the market as such. Remember, the “negative” list are items which have been withdrawn from the market for safety or efficacy reason. For them to be removed from the market, they must have first appeared on the market. Thus, the items in Category 2 will most likely never appear on the “negative” list, however, they still should not be compounded or the pharmacy runs the risk of enforcement actions by the FDA.

Great – so we have covered “negative” & “positive” lists – what’s this about demonstrably difficult?

Once again, Section 503A provide for the FDA to put together a list of categories of drugs they feel are too difficult for compounders to make. From the law:

“(3) Drug product.–A drug product may be compounded under subsection (a) only if–

(A)   such drug product is not a drug product identified by the Secretary by regulation as a drug product that presents demonstrable difficulties for compounding that reasonably demonstrate an adverse effect on the safety or effectiveness of that drug product;”

Thus, again, the FDA will put together a list, via consultation with the PCAC and via final rulemaking, a list of drug products (or categories) which compounders should not try to make. So far, the PCAC has considered to categories of drugs to add to this list: Metered Dose Inhalers and Dry Powders for Inhalation. Both categories of drugs were voted to be placed on the list. Additionally, the Committee will consider transdermal delivery systems (TDS) at the November 2016 meeting – but don’t worry – the types of transdermal drugs which will be considered are those which utilize reservoir or matrix type delivery systems. They are NOT considering transdermals which are liquids or semisolids, like gels, creams, lotions, foams, ointments or sprays. IACP fully expects the committee to recommend to add TDS to the list of demonstrably difficult drugs.

Please continue to watch for further communications from IACP regarding these “lists” and the actions of the PCAC as we continue to monitor FDA’s enforcement of Section 503A.